Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
  • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
  • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
  • C07D477/14—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

• the invention relates to new 2-substituted alkyl-3-carboxy carbapenems having the formula: with R 1 , R 2 , R 3 , X and Y defined hereafter as antibiotics and beta lactamase inhibitors produced by a novel Michael addition-elimination reaction of a substituted allyl azetidinone in the reaction shown: with R 1 , R 2 , Q, X and Y defined hereafter.
• Step 1 of Scheme 1 the propargyl azetidinone compound of Formula XX is formed on contacting the acetoxyazetidinone XVIII and the propargyl halide XIX with an elemental metal M in the presence of a Lewis acid LA wherein R 1 and R 2 are as defined hereinbefore, and R 22 is Cl, Br or I, M is Zn or Mg with Zn being preferred, LA is a suitable Lewis acid, such as, but not limited to, diethylaluminum chloride; in the presence of a suitable solvent such as tetrahydrofuran, toluene, diethyl ether or dimethoxyethane with tetrahydrofuran preferred.
• a Lewis acid such as, but not limited to, diethylaluminum chloride
• a suitable solvent such as tetrahydrofuran, toluene, diethyl ether or dimethoxyethane with tetrahydrofuran preferred
• reaction product XXII is isolated by conventional techniques in the art including dilute mineral acid wash, filtration, aqueous washing, crystallization. Yields of XXII are in the range of 30 to 80% and preferably 60-70%.
• Suitable bases that can be employed in Step 5 generally are non-aqueous ones and comprise the following:
• the allylazetidinone in Step 5 of Scheme 1 can be contacted with a range of 1.1 to 3 equivalents of a suitable base preferably 1.3 equivalents of lithium bis(trimethylsilyl)amide at a suitable temperature for time periods ranging from 0.1 to 3.0 hours, preferably 0.75 hours under an inert atmosphere of argon or nitrogen.
• a subject of this invention is a method for converting the exo-carbapenem XXVI to the endo-isomer XXVII.
• a suitable tertiary amine base in a suitable solvent in a temperature range of 0° to 40°C gives the endo-isomer XXVII over a time range of 1 to 24 hours.
• the carboxyl protecting group R 3 of these intermediates may be optionally removed by conventional procedures such as solvolysis, chemical reduction or hydrogenation.
• a protecting group such as p-nitrobenzyl, benzyl or benzhydryl which can be removed by catalytic hydrogenation
• intermediates XXVIII or XXX in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethylether-buffer, tetrahydrofuran- aqueous dipotassium hydrogen phosphate-isopropanol or the like may be treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like at a temperature from 0° to 40°C or from about 0.2 to 4 hours.
• a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like at a temperature from 0° to 40°C or
• compounds of Formulae exo-XXVIII and endo-XXX where R 3 is a physiologically hydrolyzable ester such as acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc. may be administered directly to the host without deblocking since such esters are hydrolyzed in vivo under physiological conditions.
• carbapenems exo-XXIX and endo-XXXI can be separately prepared according to Steps 9 and 10 of Scheme 1 respectively, wherein R 20 is defined as above.
• the method of deprotection as described above, will vary.
• Product isolation from the deprotection step again varies based on the method used but all methods used in this transformation follows conventional techniques in the art including chromatography and lyophilization.
• Product yields of exo-XXIX or endo-XXXI vary in the range of 10-80% with 50-60% preferable.
• Product yields vary on R 16 OH and are in the range of 20 to 85% with 50-70% being preferable. This procedure has been performed on non-related, terminal acetylenes according to J. Tsuji et. al., Tetrahedron Lett. (1980) Vol. 21, pp. 849-51. Other methods for converting a terminal acetylene to an acetylenic ester are common in the art. The above described method is preferred.
• Step 4 of Scheme 2 shows the conversion of terminal acetylene XXIII to the corresponding acetylenic amide XXXV. Similar product yields as XXXIV are realized for XXXV.
• the methodology of Scheme 2 described in Steps 3 and 4 can be further extended to the preparation of thionoester XXXVI, from the terminal acetylenic azetidinone XXIII shown in Step 5, Scheme 2.
• Dithioesters XXXVII similarly, can be prepared in Step 6.
• Step 9 the cyanoacetylene XXXIX is converted to XL by contacting XXXIX with the above mentioned reagents and conditions described in detail for Step 7, Scheme 2. Yields of the product dihalonitrile XL vary from 55 to 90%.
• the propargyl alcohol XLV is formed from XXII via a sequential treatment of XXII with two equivalents of a suitable strong base such as n-butyllithium in a suitable solvent such as tetrahydrofuran under an inert atmosphere such as argon at a temperature range of -80 to 0°C preferably -70°C.
• a suitable strong base such as n-butyllithium
• a suitable solvent such as tetrahydrofuran under an inert atmosphere such as argon
• the amount of solvent used is enough to effect solubilization of the acid XXII with an ultimate concentration range of 0.05 to 2 molar acceptable, preferably 0.1 to 0.3 molar concentration.
• Compound L is prepared when the dihalo compound XLIX is contacted with a suitable nucleophile Q in a suitable solvent, such as, but not limited to, acetone, acetonitrile, dimethoxyethane, dimethylformamide, methanol, ethanol, pyridine at a temperature range of about 0° to 80°, preferably 20° to 50°C range for a time period ranging from 1-24 hours depending on the nature of X' and Q.
• a suitable solvent such as, but not limited to, acetone, acetonitrile, dimethoxyethane, dimethylformamide, methanol, ethanol, pyridine at a temperature range of about 0° to 80°, preferably 20° to 50°C range for a time period ranging from 1-24 hours depending on the nature of X' and Q.
• a suitable solvent such as, but not limited to, acetone, acetonitrile, dimethoxyethane, dimethylformamide, methanol
• Step 1 it is the purpose of Step 1 to prepare a compound of Formula L from XLIX that possesses optimum reactivity in the Michael addition-elimination reaction that forms the 2-alkylsubstituted-3-carboxy-carbapenems.
• Step 2 of Scheme 4 compound L is contacted with an appropriate base in a suitable solvent at temperataures of -100°C to ambient. While any suitable temperature may be employed, it is preferable to use temperatures of -100° to -40° to eliminate undesired decomposition.
• the resulting Michael addition-elimination reaction produces carbapenems LI to LV in varying amounts.
• the factors that control the relative ratio of carbapenem products LII-LV in the ring closure in Step 2 include, but are not entirely confined to, structural features such as Y and X', reaction time, reaction temperature, base strength and the amount of excess base.
• Suitable bases that can be employed in Step 2 generally are non-aqueous ones and are described hereinabove for Scheme 1 - Step 5.
• suitable solvents that can be employed are generally anhydrous, aprotic solvents and are detailed hereinabove in Scheme 1 - Step 5.
• the solvent can be employed in amounts effective to solubilize the compound L.
• solutions of L in the concentration range of 0.05 to 2.0 molar are used in Step 2 of Scheme 4.
• the allylazetidinone can be contacted with a range of 1.1 to 3 equivalents of a suitable base defined above preferably 1.3 equivalents of lithium bis(trimethylsilyl)amide at a suitable temperature for time periods ranging from 0.1 to 3.0 hours, preferably 0.75 hours under an inert atmosphere of argon or nitrogen.
• a subject of this invention is a method for converting the ⁇ 1 -endo LII, (E)-exo LIII and (Z)-exo LIV isomers to the A 2- endo isomer LV. This is shown in Scheme 5.
• Intermediates LVII and LVIII, in a suitable solvent such as dioxane-water-ethanol, tetrahydrofuran-diethylether-buffer, tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol or the like may be treated under a hydrogen pressure of from 1 to 4 atmospheres in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like at temperatures from 0° to 40°C from about 0.2 to 4 hours.
• a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide or the like
• compounds of Formula exo-LVII and endo-LVIII where R 3 is a physiologically hydrolyzable ester such as acetoxymethyl, pivaloyloxymethyl, methoxymethyl, etc. may be administered directly to the host without diblocking since such esters are hydrolyzed in vitro in the presence of added esterase or in vivo under physiological conditions.
• the compounds When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
• Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
• Liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
• Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
• active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• a 4.48 g suspension of prewashed sodium hydride (50% dispersed in oil) in 200 ml of anhydrous tetrahydrofuran is cooled in an ice bath under argon.
• a solution of 10 g azetidinone prepared in Example 1 and 6.22 g bromoacetic acid in anhydrous tetrahydrofuran is stirred for an additional 20 minutes, then 16 ml dry dimethylformamide is added dropwise.
• the ice bath is then removed and the suspension is stirred overnight at room temperature.
• One hundred ml of 1 N hydrochloric acid is slowly added to the suspension followed by 200 ml water.
• the product is extracted in 3 x 300 ml of ethyl acetate.
• the organic phase is washed with 2 x 200 ml of water, 2 x 200 ml of brine, dried over magnesium sulfate and filtered.
• the filtrate is evaporated to give, after recrystallization from hot hexane, 10.9 g of product (90.2%). m.p. 86-88°C.
• the title compound is prepared by the procedure of Example 4, using 9.25 g of 3,4-dimethoxyphenyl- sulfinic acid, 6.1 g of Example 3, 3.87 g of iodine, 3.84 g of sodium bicarbonate, 3.75 g of sodium acetate, 150 ml of ethyl acetate and 75 ml of water.
• the reaction mixture is purified by flash chromatography to give 5.81 g (52%) of product.
• the title compound is prepared by the procedure of Example 4, using 2.97 g of 4-(1,1-dimethylethyl)-phenylsulfinic acid, 2.0 g of 2-chloro-2-propenyl ester, from Example 3, 1.27 g of iodine, 1.26 g of sodium bicarbonate, 1.23 g of sodium acetate, 50 ml of ethyl acetate and 25 ml of water. The reaction mixture is purified by flash chromatography to give 1.95 g (54%) of white crystalline product.
• the title compound is prepared by the procedure of Example 4, using 6.63 g of 2-thiophene sulfinic acid, 5.13 g of the (4-nitrophenyl)methyl ester from Example 3A, 2.81 g of iodine, 1.87 g of sodium bicarbonate, 3.19 g of sodium acetate, 200 ml of ethyl acetate and 50 ml of water.
• the reaction mixture is purified by chromatography to give 4.21 g (57%) of the desired product.
• Example 4 Four and twenty-three hundreths gram of iodo-sulfone prepared in Example 4 is dissolved in 45 ml of anhydrous tetrahydrofuran, under argon, and the solution is cooled to -80°C (ether/dry ice bath). To this solution is added, over a ten minute period, 7.8 ml of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. The resulting yellow solution is stirred at -80°C for one and a half hours, under argon, and then quenched with 0.53 ml of acetic acid.
• the title compound is prepared by the procedure of Example 5, using 5.7 g of iodo-sulfone from Example 4A, 60 ml of anhydrous tetrahydrofuran, 10.2 ml of 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, 0.7 ml acetic acid and 2.8 ml + 26 ml of 0.5M potassium dihydrogen phosphate.
• the reaction mixture is purified by chromatography to give 3.02 g (64%) of the pure exocyclic product as a white solid.
• the title compound is prepared by the procedure of Example 5, using 4.1 g of the iodo-sulfone from Example 4C, 50 ml of anhydrous tetrahydrofuran, 7.25 ml of 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran, 0.59 ml of acetic acid and 2 ml + 20 ml of 0.5M potassium dihydrogen phosphate. The reaction mixture is purified by chromatography to give 1.85 g of desired product as a white solid, m.p. 157-159°C.
• Example 7 The title compound is prepared by the procedure of Example 7, using 1.5 g of the exocyclic product from Example 5B, 15 ml of acetonitrile, 5.5 ml of 50% aqueous hydrogen fluoride in 49 ml of acetonitrile and excess sodium bicarbonate (to pH 7-8). 0.994 g (83%) of product is isolated without further purification.
• CI-MS m/z 499(M + NH 4 ) and 482(M + H) .
• Example 8 The title compound is prepared by the procedure of Example 8, using 0.97 g of exocyclic product from Example 7A, 5.8 ml of diisopropylethylamine and 6.8 ml of methylene chloride. 0.66 g (68%) of product is isolated without further purification.
• the title compound is prepared by the procedure of Example 9, using 0.366 g of the endocyclic product from Example 8, 4.5 ml of ethyl acetate, 4.5 ml of methylene chloride, 0.027 g of triphenylphosphine, 0.237 g of potassium 2-ethylhexanoate and 0.045 g of tetrakis(triphenylphosphine)palladium catalyst. 0.828 g (25%) of product is isolated after reverse phase thin layer chromatography (water/ethanol:95/5).
• the title compound is prepared by the procedure of Example 9, using 0.660 g of the endocyclic product from Example 8A, 8 ml of ethyl acetate, 8 ml of methylene chloride, 0.52 g of triphenylphosphine, 0.278 g of potassium 2-ethylhexanoate and 0.052 g of tetrakis(triphenylphosphine)palladium catalyst. 0.1194 g (20%) of product is isolated after reverse phase thin layer chromatography (water/ethanol 75/25).
• Example 7 Following the procedure of Example 7, 0.614 g of the exocyclic product of Example 5C, 10 ml of acetonitrile, 8 ml of 50% aqueous hydrogen fluoride in 42 ml of acetonitrile and excess sodium bicarbonate (to pH 7-8) is reacted. 0.405 g (81 %) of the desired product is obtained and used in the following reaction without purification.
• the title compound is prepared by the procedure of Example 4, 0.87 g of the p-methoxybenzyl ester from Example 23, 0.63 g of sodium 4-toluenesulfinate dihydrate, 0.50 g of iodine, 0.25 g of sodium acetate in 12 ml of ethyl acetate and 6 ml of water is irradiated with a 300 W bulb for 45 minutes. After purification, 1.04 g (73%) of product is obtained as an oil.
• Example 5 The title compounds are prepared by the procedure of Example 5, using 2.3 g of iodo-vinyl sulfone from Example 11, 25 ml of anhydrous tetrahydrofuran and 4.7 ml of a 1 M solution of lithium bis-(trimethylsilyl)amide in tetrahydrofuran.
• the product as an oil, consists of a mixture of the 2 isomers weighing 1.0 g after purification by flash column chromatography.
• a 0.450 g sample of the isomeric mixture prepared in Example 12 is dissolved in a solution of 13 ml of tetrahydrofuran and 0.63 ml of acetic acid. To this is added 3.6 ml of 1M tetra-n-butylammonium fluoride/tetrahydrofuran solution according to the procedure outlined in J. Med. Chem. (1987) 30,879. After the prescribed workup and purification, 0.244 g (67%) of product is obtained as an oil.
• Example 13 Applying the same experimental conditions as in Example 28 as well as that detailed in J. Org. Chem. (1984), 49, 5271, 0.20 g of the carbapenem ester prepared in Example 13 is dissolved in 2.6 ml of anisole and 1 ml of methylene chloride at -50° under an inert atmosphere. To this is added 0.190 g of anhydrous aluminum chloride. The reaction product is isolated as its sodium salt and weighs 0.044 g (27%).
• the title compound is prepared by the procedure of Example 8, reacting 0.283 g of the carbapenem ester prepared in Example 13, with 2.0 ml of diisopropylethylamine in 5 ml of methylene chloride for 16 hours at 45°C to give 0.110 g of the product (39%) after purification.
• Example 14 The title compound is prepared by the procedure of Example 14, 0.10 g of the carbapenem ester prepared in Example 15 is hydrolyzed to give 0.030 g (38%) of product as the sodium salt.
• the title compound is prepared by the procedure of Example 4, using 1.4 g of the 2-chloroallyl ester from Example 3, 1.4 g of 4-acetamidobenzenesulfinic acid, 0.89 g of iodine, 0.30 g of sodium bicarbonate and 0.89 g of sodium acetate in 20 ml of ethyl acetate and 10 ml of water. After purification, 1.85 g (73%) of product is obtained as an oil.
• the title compound is prepared by the procedure of Example 5, using 1.78 g of the iodovinyl sulfone from Example 17, 18 ml of anhydrous tetrahydrofuran and 5.7 ml of a 1M solution of lithium bis-(trimethylsilyl)amide in tetrahydrofuran. After purification, 0.25 g (17%) of the product is obtained.
• the title compound is prepared by the procedure of Example 6, reacting 0.251 g of the carbapenem from Example 18, 8 ml anhydrous tetrahydrofuran, 0.37 ml of acetic acid, 2.1 ml of a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran for 7 hours at 20° under an inert atmosphere; then storing overnight at 4°C. The reaction is purified to give 0.115 g (57%) of desired product and 0.042 g of unreacted starting material.
• the title compound is prepared by the procedure of Example 9 and in J. Med. Chem. (1987)30, 879, using 0.105 g of the hydroxyethyl carbapemen from Example 19, 0.013 g of tetrakis(triphenylphosphine) palladium, 0.006 g of triphenylphosphine, 0.045 g of potassium 2-ethylhexanoate in 2 ml of ethyl acetate and 2 ml of water. The reaction mixture, after work up, gives 0.040 g (41 %) of desired product.
• Example 3A To a 50 ml methanolic solution containing 2.5 g of the acetylenic ester prepared in Example 3A is added 0.1 gm palladium chloride, 1.6 g anhydrous cupric chloride and 1.1 g sodium acetate. The reaction solution is degassed 3 times using carbon monoxide. Then the reaction flask is fitted with a balloon containing approximately 300 ml gaseous carbon monoxide. The reaction is stirred under this carbon monoxide atmosphere until the green reaction color turns to black. Tlc monitoring indicates all starting acetylene to be consumed. The reaction mixture is poured over a mixture of ice water and diethyl ether. Following an aqueous workup and purification via flash column chromatography, a colorless crystalline material 2.0 g (71 %) is isolated, m.p. 55°C.
• the title compound is prepared by the procedure of Example 4, using 3.94 g of the product from Example 23, 2.18 g of sodium benzenesulfinate, 2.24 g of iodine and 1.45 g of sodium acetate. The mixture is purified by chromatography to give 5.29 g (84%) of the desired product as a pale yellow oil.
• the title compound is prepared by the procedure of Example 5, using 3.18 g of the product from Example 24, 30 ml of anhydrous tetrahydrofuran, 6.68 ml of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran, 0.45 ml of glacial acetic acid and 1.5 ml + 15 ml of 1 M potassium dihydrogen phosphate.
• the 2.69 g isomeric mixture is slurried with 25% ethyl acetate/hexane to give 0.798 g (30.5%) of the exocyclic product as a white solid.
• the filtrate is concentrated to give 1.83 g (70%) of the endocyclic product as an oil.
• the title compound is prepared by the procedure of Example 6, using 0.50 g of the product from Example 25, 17 ml of tetrahydrofuran, 4.27 ml of 1 M tetrabutylammonium fluoride and 0.74 ml of glacial acetic acid. The mixture is purified by flash chromatography to give 0.148 g (37%) of the desired product.
• the title compound is prepared by the procedure of Example 4, using 4.6 g of the 4-nitrobenzyl ester prepared as described in Example 3A, 4.2 g of 4-(trifluoromethyl)benzenesulfinic acid, 1.5 g of sodium acetate, 0.84 g of sodium bicarbonate, 2.0 g of iodine, 75 ml of ethyl acetate and 35 ml of water. The mixture is purified by chromatography to give 7.7 g (95%) of the desired product.
• the title compound is prepared by the procedure of Example 5, using 7.0 g of product from Example 29, 75 ml anhydrous tetrahydrofuran, 11.3 ml of a 1M solution of lithium bis(trimethylsilyl)amide, 0.94 ml of acetic acid, 12.2 ml of potassium dihydrogen phosphate and 180 ml of ethyl acetate.
• the reaction mixture gives 6.2 g (93%) of exocyclic:endocyclic product.
• a 2 g aliquot is purified by chromatography to give 0.15 g (9%) of the exocyclic product as colorless crystals.
• a 1.5 g fraction is isolated as a mixture of exocyclic:endocyclic compound, which is reacted in Example 31.
• Example 6 The title compound is prepared by the procedure of Example 6, using 0.62 g of product from Example 31, 18 ml of anhydrous tetrahydrofuran, 0.79 ml of glacial acetic acid and 4.6 ml of a 1M solution of tetra-n-butylammonium fluoride. The reaction mixture gives 0.57 g (100%) of product which is used immediately in Example 33 without further purification.
• a mixture of 0.57 g of product from Example 32, 20 ml of dioxane, 5 ml of water, 0.078 g of sodium bicarbonate and 0.150 g of palladium hydroxide is hydrogenated in a Parr apparatus at 21 lbs. psi for 1 hour.
• the reaction mixture is filtered through a pad of diatomaceous earth and the pad is washed with water and diethyl ether.
• the aqueous layer is extracted with 20 ml of diethyl ether and 2 x 20 ml of ethyl acetate.
• the aqueous phase is filtered through a pad of diatomaceous earth and lyophilized to give 0.255 g of a pale yellow solid.
• the solid is purified by reverse phase chromatography to give 0.020 g of the desired product as a white solid.
• Example 7 The title compound is prepared by the procedure of Example 7, using 0.78 g of the exo compound from Example 35 and aqueous hydrogen fluoride in acetonitrile to give 0.48 g (76%) of product.
• the 300 Mhz nuclear magnetic resonance spectrum of this compound was essentially identical to that described in Example except for the absence of the t-butyldimethylsilyl group.
• the title compound is prepared by the procedure of Example 41, using 0.45 g of product from Example 40, 5 ml of tetrahydrofuran, 1.6 ml of 1M sodium bis(trimethylsilyl)amide, 0.2 ml of glacial acetic acid, 10 ml of 0.5M potassium hydrogen phosphate and 20 ml ethyl acetate.
• the reaction mixture is purified by flash chromatography to give 0.165 g (39%) of desired product.
• Example 41 The title compound is prepared by the procedure of Example 41, using 0.165 g of product from Example 42, 0.041 g (40 ⁇ l) of 1,8-diazobicyclo[5.4.0]undec-7-ene, 20 ml of diethyl ether. The organic layer is concentrated in vacuo to give 0.140 g (85%) of product as a white foam.
• the title compound is prepared by the procedure of Example 33, using 0.134 g of product from Example 43, 0.050 g of 10% palladium hydroxide/carbon, 0.021 g of sodium bicarbonate, 2.5 ml of dioxane and 2.5 ml of water at 40 lbs. psi for one hour.
• the aqueous layer is purified by reverse phase chromatography (water:ethanol, 95:5).
• the aqueous extract is lyophilized to give 0.020 g of the desired product.
• Example 4 In a similar fashion as described in Example 4, 1.1 g of the terminal acetylene prepared in Example 3A, is reacted with 0.61 g iodine and 1.05 g sodium 4-fluorophenylsulfinate to give 1.45 g of the desired product after an aqueous workup and purification.
• Example 46 In a similar fashion as described in Example 5A, 1.4 g of the iodo-vinyl sulfone prepared in Example 46 is reacted with 1.3 equivalents of lithium bis(trimethylsilyl)amide at -78°C for 1 hour to give 0.675 g of the desired product.
• Example 7 In a similar fashion as described in Example 7, 0.25 g of the exocyclic carbapenem prepared in Example 46 is reacted with hydrogen fluoride dissolved in acetonitrile to give the exo-6-(1-hydroxyethyl) derivative which is carried on into the diisopropylethylamine isomerization step in similar fashion as described in Example 8 to give 0.138 g desired product.
• Example 47 0.173 g of the carbapenem prepared in Example 47 is reacted with hydrogen (2 atmospheres pressure) and 0.059 g palladium hydroxide catalyst for 0.75 hour to give 0.12 g desired product.
• the cooling bath is removed and the mixture is diluted with ethyl acetate, water and 0.05 ml of glacial acetic acid. After vigorous stirring, the mixture is partitioned and the organic layer washed with water and brine. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo.
• the crude product is dissolved in 3 ml of tetrahydrofuran and treated with 0.18 g of solid diphenyl- diazomethane. After the visible signs of nitrogen evolution have ceased, the reaction is warmed to 60°C for 45 minutes. The mixture is cooled to room temperature, concentrated in vacuo and chromatographed on silica gel with 20% ethyl acetate/hexane to give 0.174 g (28%) of the desired product.
• Examples 53 to 113 describe compounds of Formula LXII which are obtained by the methodology described hereinabove.

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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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ID=24017956

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Citations (7)

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• 1990
  • 1990-04-10 US US07/507,271 patent/US5068232A/en not_active Expired - Fee Related
• 1991
  • 1991-02-19 IL IL9727591A patent/IL97275A/en not_active IP Right Cessation
  • 1991-02-21 EP EP19910102512 patent/EP0478874A3/en not_active Ceased
  • 1991-02-26 TW TW080101501A patent/TW229209B/zh active
  • 1991-02-28 IE IE067691A patent/IE910676A1/en unknown
  • 1991-03-27 NZ NZ237610A patent/NZ237610A/en unknown
  • 1991-04-04 SK SK929-91A patent/SK278900B6/sk unknown
  • 1991-04-04 CZ CS91929A patent/CZ280808B6/cs not_active IP Right Cessation
  • 1991-04-05 JP JP3102060A patent/JPH04234885A/ja active Pending
  • 1991-04-08 PH PH42262A patent/PH27462A/en unknown
  • 1991-04-08 CA CA002039968A patent/CA2039968A1/en not_active Abandoned
  • 1991-04-09 FI FI911701A patent/FI95256C/fi active
  • 1991-04-09 AU AU74248/91A patent/AU634876B2/en not_active Ceased
  • 1991-04-09 PT PT97301A patent/PT97301B/pt not_active IP Right Cessation
  • 1991-04-09 ZA ZA912629A patent/ZA912629B/xx unknown
  • 1991-04-09 HU HU911141A patent/HU215606B/hu not_active IP Right Cessation
  • 1991-04-09 KR KR1019910005684A patent/KR0183020B1/ko not_active IP Right Cessation
  • 1991-04-09 NO NO911368A patent/NO178624C/no unknown
  • 1991-04-10 PL PL91289814A patent/PL166336B1/pl unknown
  • 1991-04-10 PL PL91294072A patent/PL165952B1/pl unknown
  • 1991-04-10 CN CN91102357A patent/CN1034332C/zh not_active Expired - Fee Related
  • 1991-04-10 PL PL91294071A patent/PL165937B1/pl unknown
• 1993
  • 1993-07-06 US US08/087,944 patent/US5369102A/en not_active Expired - Lifetime
• 1994
  • 1994-04-28 US US08/234,905 patent/US5480987A/en not_active Expired - Fee Related
  • 1994-10-12 CN CN94116618A patent/CN1034329C/zh not_active Expired - Fee Related
  • 1994-10-12 CN CN94116619A patent/CN1037177C/zh not_active Expired - Fee Related

Patent Citations (7)

Non-Patent Citations (3)

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